Esterification reaction, which is the most basic reaction of organic synthesis, is an important reaction having a great utility value also from the view point of an environmentally-friendly chemical process. An enormous amount of reports have already been made concerning the esterification reaction, but there were problems as follows in view of green chemistry and atom efficiency: one equivalent weight or more of condensing reagent or activator was used for a substrate in many cases; a large quantity of by-products was generated through the reaction, thereby complicated operations for separation and purification become necessary after the reaction; unless either of carboxylic acid or alcohol was used excessively, it was impossible to prepare ester efficiently in many cases (see, e.g., Japanese Laid-Open Patent Application No. 52-75684; Synthesis. 1978, p. 929; Chem. Lett. p. 55, 1977; Chem. Lett. p. 663, 1981; Tetrahedron. Lett. 28, p. 3713, 1987; and J. Org. Chem. 56, p. 5307, 1991). Excessive use of substrates should actually be avoided, so it would be an ideal process if a direct esterification could be performed from equimolar amounts of carboxylic acid and alcohol. A polyester polymerized catalyst comprising a structure of Ar—O— (Ar represents an aryl group) and the like and one or more of metal compounds selected from the group of scandium, yttrium, zirconium, hafnium, and vanadium, and (see, e.g., Japanese Laid-Open Patent Application No. 2000-154241) is known as a polycondensation catalyst. Additionally, as a method for preparing ester wherein ester can be synthesized in good yield even when approximately equimolar amounts of the raw materials, i.e. acids and alcohols, are used, a method for preparing ester from carboxylic acids and alcohols using an esterification catalyst containing a titanium metal compound selected from the group of halides, nitrate salts, carboxylate salts, alcoholates and acetylacetone-type complex of titanium metal, as at least one of the active ingredients (see, e.g. Japanese Laid-Open Patent Application No. 8-71429) is also known.
Other than those above, followings are known: an ester polycondensation catalyst comprising an aluminum compound and a metal compound other than aluminum (see, e.g., Japanese Laid-Open Patent Application No. 2000-302854), a method for preparing an aliphatic polyester, wherein a germanium compound and at least one of the metal compounds selected from the group of titanium, antimony, zirconium, iron and the like, are used as a catalyst (see, e.g., Japanese Laid-Open Patent Application No. 8-27262), a catalyst for preparing polyester, wherein a compound comprising at least one of the elements selected from the group of beryllium, magnesium, calcium, hafnium, iron and the like and a hydrolysate of a titanium halide (see, e.g., Japanese Laid-Open Patent Applications Nos. 2001-48973 and 2001-64377), and a transesterification catalyst, wherein phosphate ion is contained in one or more of metal oxide and/or metal hydroxide selected from the group of aluminum, zirconium and iron (see, e.g., Japanese Laid Open-Patent Application No. 2001-17862).
However, there was no catalyst as the one used in the above-mentioned esterification reaction with the following features: selective synthesis of ester can be realized in good yield even by using approximately equimolar amounts of carboxylic acid and alcohol as the raw materials; the reaction speed was high at low temperature even when a small amount of catalyst are used; a very small side reaction was occurred; and the catalyst which was reusable by simple processing was used repeatedly, thereby the usage of the catalyst could be significantly reduced.
Since the demand for compounds having complicated structures is increasing for the synthesis of pharmaceuticals, the object of the present invention is to provide a method for preparing an ester condensate and a catalyst therefore; wherein the method enables to synthesize enormous amounts of ester condensates comprising a specific structure in good yield, by a reaction of carboxylic acids and alcohols in equimolar amounts, while generation of by-products is prevented in the synthesis of organic compounds such as the pharmaceuticals; and wherein the catalyst exhibits a good catalytic efficiency as a catalyst for use, the use of the catalyst in small amount is sufficient, and the catalyst being reusable can be used repeatedly; therefore, the method for preparing an ester condensate can be applied to industrial methods which are preferable also in view of green chemistry.
The present inventors have already developed a dehydration-condensation reaction from an-equimolar mixture of carboxylic acid and alcohol, wherein zirconium(IV) salt or hafnium(IV) salt was used for the catalyst. Having promoted the study on esterification reaction, the present inventors performed a condensation reaction as follows: Zr(OH)x(OAc)y (x+y=4) as a catalyst was added to a heptane solution of an-equimolar mixture of 4-phenylbutyric acid and cyclododecanol, further 2 mol % of various metal salts as additives were added thereto, the mixture was heated to ref lux (the bath temperature: 120° C., 6 hours), and the resultant was brought to azeotropic dehydration. As a result, it was revealed that the catalytic activity is improved by adding metal salts such as Ga(Oi-Pr)3, Fe(Oi-Pr)3, Al(Oi-Pr)3, Sn(Oi-Pr)4 and the like as additives. Among those metal salts, using Ga(Oi-Pr)3 and Fe(Oi-Pr)3 brought particularly good results. Single use of 3 mol % of these additives for performing the reaction in stead of Zr(IV) salt could not induce excellent activity. Although Ti(Oi-Pr)4 is also known as a catalyst having high activity as well as Zr(IV) or Hf(IV) salts, synergistic improvement of the catalytic activity could not be observed by using the combinations of Ti(IV)-Zr(IV), Zr(IV)-Hf(IV), and Ti(IV)-Hf(IV). When the reaction was performed similarly by using Hf(IV) salt, a similar effect to the additive effect on Zr(IV) salt could be obtained.
Next, the relationship between content rate to 10 mol % of Zr(Oi-Pr)4 and the catalytic activity was investigated on Fe(Oi-Pr)3 which showed the most significant additive effect. As the result, it was shown that adding Fe(Oi-Pr)3 into Zr(Oi-Pr)4 little by little improved the catalytic activity which kept enhancing until the content rate of Fe(Oi-Pr)3 reached to 0.5 mol %; even if the rate of Fe(Oi-Pr)3 was further increased, the catalytic activity showed little change. Accordingly, it is substantially appropriate that the molar ratio of Zr(Oi-Pr)4 to Fe(Oi-Pr)3 is between 20 to 1 and 1 to 1.
Next, the change with time was studied on ester condensation reaction using composite metal salt catalysts, Zr(Oi-Pr)4—Fe(Oi-Pr)3, Hf(Oi-Pr)4—Fe(Oi-Pr)3, and Ti(Oi-Pr)4—Fe(Oi-Pr)3. As the result, it was revealed that Zr(IV)-Fe(III) had approximately equal level of catalytic activity to that of Hf(IV)-Fe(III); a significant accelerating effect of the reaction could not be observed with Ti(IV)-Fe(III).
Further, as the result of consideration of reusability of catalysts in order to promote green chemistry, it was demonstrated that solids had an equivalent catalytic effect to that of Zr(Oi-Pr)4—Fe(Oi-Pr)3, which was resulted by adding 1 M hydrochloric acid solution to the mixture of Zr(Oi-Pr)4 or Hf(Oi-Pr)4 and Fe(Oi-Pr)3, stirring the admixture for 0.5 hour at room temperature, and then exsiccating it. Consequently, ester condensation reaction was carried out with 3 mol % of Zr(Oi-Pr)4 and 4 mol % of Fe(Oi-Pr)4, then 1 M hydrochloric acid solution was added thereto and ester was obtained from the organic layer by extraction. On the other hand, metal salt was recovered from the aqueous layer, carboxylic acid, alcohol and a reaction solvent were added to the aqueous solution again without concentration, and azeotropic dehydration was carried out by heating to reflux. It was followed by ester condensation reaction proceeding as in the case of the first reaction. The present inventors obtained knowledge that the catalyst can be recovered and reused by repeating this series of operations.
In addition, from the result of considering reusability of a catalyst without using hydrochloric acid, esterification reaction was carried out under heating to ref lux with the use of the mixture of Zr(Oi-Pr)4 or Hf(Oi-Pr)4 and Fe(Oi-Pr)3 as a catalyst with azeotropic dehydration in a mixed solvent of a low-polar organic solvent and an ionic liquid. After the reaction was finished, the solution was left at room temperature for sometime, and then it was found that the solution was separated into two layers of an organic solvent layer and an ionic liquid layer. Ester was obtained from the organic layer in the upper part in good yield. On the other hand, carboxylic acid, alcohol and a reaction solvent were added to the solution again without concentrating the ionic liquid layer containing metal salts, and azeotropic dehydration was carried out by heating to reflux. It was followed by ester condensation reaction proceeding as in the case of the first reaction. The present inventors obtained knowledge that the catalyst can be recovered and reused by repeating this series of operations, which led the present inventors to complete the present invention.